Numerous studies have established a clear link between key hemostatic system components and tumor progression. A mechanism underlying this relationship was recently illuminated by studies showing that platelet activation and fibrinogen facilitate metastasis by impeding the clearance of newly formed micrometastases by natural killer (NK) cells. However, the machinery used by tumor cells to engage the host hemostatic system and the mechanisms linking platelets and fibrinogen to diminished natural killer cell function remain undefined. A likely means available to tumor cells for engaging hemostasis is expression of tissue factor (TF), the cell-associated initiator of coagulation. Although there is substantial evidence linking TF expression by tumor cells to metastasis, it remains unclear if TF supports tumor spread by mechanisms linked to its function in coagulation or TF-mediated processes uncoupled from hemostasis. The planned experiments will use in vivo models of tumor progression and transgenic mice to explore the importance of interplay amongst tumor associated TF, circulating hemostatic system components, and innate immune surveillance mechanisms in determining metastatic potential. The proposed studies will test the following hypotheses: 1) Tumor cell associated TF enhances metastatic potential by a mechanism linked to thrombin generation, local platelet-fibrin thrombus formation and subsequent suppression of NK cell mediated clearance of micrometastases, 2) NK cell engagement of activated platelets and/or fibrinogen or exposure to platelet derived soluble factors results down-regulation of NK cell function. These studies will deepen our understanding of the metastatic process and shed light on important crosstalk mechanisms between the hemostatic and innate immune systems. The knowledge gained could point to novel therapeutic targets to treat or prevent metastatic disease. Relevance to public health: The spread of cancer to distant organs (i.e. metastasis) is a major cause of cancer deaths. Cancer cells can facilitate this process by subverting the host clotting system, which can serve to protect them from immune cells capable of recognizing and killing tumor cells. A deeper understanding of how clotting factors contribute to cancer spread could lead to novel therapies designed to treat or prevent metastases.